Methods and systems for operating an aerosol generator

ABSTRACT

A nebulized fluid, generated by vibrating an aerosolization element, is introduced into a breathing circuit during a certain interval of a patient&#39;s breathing cycle. In some embodiments, the fluid comprises an antibiotic that is selected to treat a pulmonary infection resulting from mechanical ventilation.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of application Ser. No.10/996,994, entitled “Methods and Systems for Operating an AerosolGenerator”. The disclosure of that application is incorporated herein inits entirety.

The present application is related to pending U.S. patent applicationSer. No. 09/876,542, filed Jun. 7, 2001, Ser. No. 09/876,402, filed Jun.7, 2001, and Ser. No. 09/812,987, filed Mar. 20, 2001, the completedisclosures of which are incorporated herein by reference.

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 09/849,194, filed May 4, 2001, which claims thebenefit of Ireland patent application No. PCT/IE/00051, filed May 5,2000, which are incorporated herein in their entirety.

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 09/812,755, filed Mar. 20, 2001, which isincorporated herein in its entirety.

The present application is a continuation-in-part and claims the benefitof U.S. Provisional Application 60/349,763, filed Jan. 15, 2002, whichis incorporated herein in its entirety.

The present application is a continuation-in-part and claims the benefitof U.S. Provisional Application Nos. 60/349,805, filed Jan. 15, 2002;60/380,655, filed May 14, 2002; 60/408,743, filed Sep. 5, 2002; and60/439,045, filed Jan. 8, 2003, entitled “Methods and Systems forOperating an Aerosol Generator”, which are incorporated herein in theirentirety.

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 10/284,068, filed Oct. 30, 2002, which claims thebenefit of U.S. Provisional Application Nos. 60/344,484, filed Nov. 1,2001 and 60/381,830, filed May 20, 2002, which are incorporated hereinin their entirety.

BACKGROUND OF THE INVENTION

The present invention is generally related to liquid aerosol generators.In particular, the present invention is related to methods and devicesfor identifying the contents of a nebule to improve the delivery of theaerosolized liquid to the patient.

The ability to aerosolize or nebulize small liquid droplets is importantin a variety of industries. Merely by way of example, manypharmaceuticals can now be delivered to the lungs in liquid droplet formthrough use of an aerosol generator, such as a nebulizer inhaler.Aerosolization is also a useful technique to dispense deodorizers,perfumes, insecticides, or the like, into the atmosphere or to othertarget areas.

Aerosol generators can be configured to deliver a number of differentpharmaceutical aerosols to the patient's lungs or other target areas ofthe body. Typically, the aerosol generator will utilize a removablesupply of a liquid pharmaceutical that is contained in some type ofportable nebule, such as an ampoule, container, canister, reservoir, orthe like.

While the existing aerosol generators have proven to be effective, theexisting aerosol generators suffer some limitations. One problem withexisting aerosol generators is that users may inadvertently install andnebulize an incorrect drug nebule into the aerosol generator. As can beappreciated, delivery of the wrong drug can be extremely dangerous, ifnot fatal.

Another problem with existing aerosol generators is that the aerosolgenerator cannot identify the liquid in the nebule. Consequently, it hasproven to be difficult to provide an efficient delivery of theaerosolized pharmaceutical to the patient. Since some of thepharmaceuticals to be aerosolized may be more effective when deliverednear the beginning of a patient's breathing cycle, while otherpharmaceuticals may be more effective when delivered near the end of thepatient's breathing cycle it is preferable that the aerosol generator beable to identify the type of liquid disposed in the nebule so that thecorrect delivery sequence can be chosen to deliver the aerosol to thepatient. While the existing nebulizers have proven to be effectivewithin certain parameters, the existing nebulizers also presentopportunities for improvements.

One area for improvement is the calculation and control of the precisetime of aerosol delivery within a user's or patients breathing cycle.This is especially in issue with respect to patients that receive someof all of their inspiratory air from a ventilator device. Existingnebulizers may deliver a constant flow of aerosol into the ventilatortubing, which can lead to a significant amount of aerosol lingering inthe tubing or other elements of the overall ventilator system—thislingering aerosol may not be inhaled, as it collects while the patientis exhaling or otherwise not inhaling, resulting in a significant amountof aerosolized medication being pushed out of the system, such as duringexhalation, without being inhaled by the patient. Such situations areproblematic for a number or reasons. First, the dosage of drug thatactually is inhaled by the patient may be significantly inaccuratebecause the amount of medication the patient actually receives into thepatient's respiratory system may vary with fluctuations of the patient'sbreathing pattern. Further, a significant amount of drug that isaerosolized may end up being wasted, and certain medications are quitecostly, thus health-care costs can be escalated. Further still, unusedaerosolized medication will typically be released to the ambientatmosphere with a patent's exhalation. This can end up medicatingindividuals in the patient's surroundings and this may give rise toadverse effects with respect to such individuals. Moreover, in ahospital environment such individuals may be either health-careproviders, who could be exposed to such air pollution over a prolongedperiod of time, or other patients, who may be in a weakened condition orotherwise overly sensitive to exposure to non-prescribed or excessiveamounts of a medication.

For these reasons, it is desired to provide an aerosol generator thatcan obtain information about the contents of the nebule. In particular,it is desired to provide methods and devices, which can determine thetype of liquid disposed in the drug so as to provide an improved levelof safety to the patient and an increased efficiency in the delivery ofthe aerosol to the patient. Further, for these reasons, it is desired toprovide methods and devices that can provide aerosol to a patient at aselected interval of the breathing cycle. It is also desired to providemethods and devices that can provide aerosol to a patient at a selectedinterval wherein the interval is selected based on the identity of thedrug to be administered.

BRIEF SUMMARY OF THE INVENTION

The present invention provides devices and methods for improving a levelof safety to the patient and for providing an increased efficiency ofdelivery of an aerosol to the patient

In one method, the present invention provides a method of creating anaerosol. The method comprises providing an aerosol generator andcoupling a nebule to an interface of the aerosol generator. Anidentification marker is read on the nebule and the aerosol generator isoperated according to an operation program based on the information readfrom the identification marker on the nebule.

In another method, the present invention provides a method of nebulizinga liquid. The method comprises taking one or more breaths and measuringcharacteristics of the breath. Another breath is taken and an aerosolgenerator is operated based on the measured characteristics of the oneor more measured breaths.

In yet another method, the present invention provides a methodcomprising providing a nebulizer system comprising a housing, an aerosolgenerator, a controller coupled to the aerosol generator, and areservoir in communication with the aerosol generator. A nebule having abody and a keying element is provided. The nebule is inserted into thehousing so that the key element provides access to the reservoir whenproperly keyed with the housing. The liquid is transferred from thenebule into the reservoir and the aerosol generator is operated with thecontroller to aerosolize the liquid.

In another aspect, the present invention provides an aerosol generatorcomprising an interface. A sensing device is coupled to the aerosolgenerator. An ampoule having at least one identification marker that candetected by the sensing device is attachable to the interface.

In another aspect, the present invention provides a nebulizer systemcomprising a housing that defines a passageway that is adapted todeliver an aerosolized liquid to a user. An aerosol generator ispositioned to provide an aerosolized liquid into the passageway. Acontroller having a memory and a plurality of aerosol generatoroperation programs that control operation of the aerosol generator iscoupled to the aerosol generator. A reader is configured to read anidentification marker on a nebule having a supply of liquid for theaerosol generator, and is configured to send information from theidentification marker to the controller. Typically, the controller isfurther configured to operate the aerosol generator according to one ofthe operation programs based on the information from the marker.

In another aspect, the present invention provides a nebule comprising anebule body holding a liquid that is adapted to be supplied to anaerosol generator of a nebulizer; and an identification marker on thenebule body, the identification marker having information identifyingthe liquid, wherein the identification marker is readable by a nebulizerto control operation of the aerosol generator based on the information.

In another aspect, the present invention provides a nebulizing elementpositioned to provide nebulized fluid into a ventilator breathingcircuit to provide nebulized fluid to a patient receiving air from aventilator. It will be appreciated that a nebulizing element may also bereferred to herein a an aerosolization element, and a ventilator mayalso be referred to herein as a respirator.

In another aspect, the present invention provides operation sequences bywhich aerosol is provided a predetermined points in a breath cycleprovided by a ventilator. In one aspect, the present invention providesfor an operation sequence in which aerosol production begins at apredetermined point within an inhalation phase, which may also bereferred to herein as an inspiratory phase, and stops at a secondpredetermined point within the same inhalation phase. In another aspect,the present invention provides for an operation sequence, which may bereferred to as an operation program, in which aerosol production beginsat a predetermined point in an inhalation phase and stops at a pointafter the inhalation phase has ended, i.e. at a certain point in theexhalation phase. It will be appreciated that the exhalation phase mayalso be referred to as the expiratory phase, and may encompass theentire period of time during which no inhalation phase is taking place;in other words, the exhalation phase may include not only the actualexhalation of the patient, but also any pause that may occur before orafter exhalation. In another aspect, the present invention provides anoperation sequence in which aerosolization begins at a predeterminedpoint within the exhalation phase and stops within that exhalationphase, or, alternatively, begins at a predetermined point within anexhalation phase and stops at a predetermined point in the succeedinginhalation phase.

In another aspect, the present invention provides for selection of aparticular operating sequence from a plurality of available operatingsequences. Similarly, the present invention provides for modes ofoperation, which modes may include one or more operating sequences.

In another aspect, the present invention provides for algorithms to setforth operation sequences, choice of operation sequences or choice ofmodes of operation.

In another aspect, the present invention provides for consideration ofthe identity of a drug to be administered in executing an algorithm,choosing a mode of operation, or selecting or running an operationsequence.

In another aspect, the present invention provides for nebulization ofparticular drug groups or drugs, such as, for example, antibodies, suchas IgG or antibiotics, such as aminoglycosides, such as amikacin.

In another aspect, the present invention provides for a nebulizeddroplet ejection device for use with a ventilator, wherein the deviceproduces droplets by a vibratory apertured element during a selectedinterval of a breathing cycle.

In another aspect, the present invention provides for apparatus andmethods for varying the particle size distribution of a nebulized mistby varying the aperture exit diameter of an apertured vibratoryaerosolization element.

For a further understanding of the nature and advantages of theinvention, reference should be made to the following description takenin conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically shows a system of the present invention;

FIGS. 2 to 4 illustrate an exemplary nebule and feed system interface ofthe present invention;

FIG. 5 shows an elevational view of another exemplary system of thepresent invention comprising an electromechanical sensor;

FIG. 6 shows a plan view of an ampoule and an electromechanical sensorof FIG. 5;

FIGS. 7 and 8 show an ampoule and feed system interface having analternative threaded interface;

FIG. 9 is a cross sectional plan view illustrating another ampoule andfeed system interface;

FIG. 10 is a plan view of an ampoule having an identification markerdisposed in a non-helical configuration;

FIG. 11 illustrates a simplified flowchart illustrating one exemplarymethod of the present invention;

FIG. 12 illustrates another simplified method of the present invention;

FIG. 13 illustrates yet another simplified method of the presentinvention; and

FIG. 14 illustrates another simplified method of the present invention.

FIG. 15 is a graph showing various modes of aerosolization over thecourse of breathing cycles;

FIG. 16 a is a schematic cross-sectional representation of an aerosolgenerator in accordance with the present invention;

FIG. 16 b is a schematic cutaway cross-section detail of the aerosolgenerator represented in FIG. 16 a.

FIG. 17 is a schematic perspective view of a nebulizer incorporated intoa ventilator breathing circuit in accordance with the present invention;

FIG. 18 is a schematic representation of algorithms of operatingsequences in accordance with the present invention;

FIG. 19 s an alternative schematic representation of the representationof FIG. 18;

FIG. 20 is a further schematic representation of algorithms of operatingsequences shown in FIG. 19 and in accordance with the present invention.

FIG. 21 is a schematic representation of an algorithm by which anoperating sequence may be chosen base on the combination of a pluralityof independent sets of information.

DETAILED DESCRIPTION OF THE INVENTION

The aerosol generator systems of the present invention, in one aspect,include an aerosol generator coupled to a controller that is incommunication with at least one sensor such that delivery sequence ofthe aerosol to the patient can be based at least in part on theinformation obtained with the sensors. In some exemplary embodiments,the system includes a nebule identification sensor to read anidentification marker on the nebule so as to identify the type of liquidthat is disposed within the nebule. In other exemplary embodiments, thesystem includes a breathing characteristic sensor that monitors andrecords the breathing characteristics of the patient so as to allow thecontroller to direct the delivery of the aerosol to coincide with thepatient's breathing pattern. In yet other exemplary embodiments, theaerosol generator system includes both a nebule identification sensorand a breathing characteristic sensor.

FIG. 1 schematically illustrates an exemplary aerosol generating system20 of the present invention. The system 20 includes an aerosol generator(AG) 22 that is in communication with an output passageway 24, such as aventilator circuit, mouthpiece, face mask, or the like. A nebule 28containing a liquid can be removably coupled to a feed system interface26 to deliver a liquid to aerosol generator 22 for aerosolization. Acontroller 30 is in communication with aerosol generator 22 to controlthe sequence of aerosolization of the liquid to the patient. Controller30 can be coupled to a breathing sensor 32 that is in communication withoutput passageway 24 so as to monitor the breathing characteristics ofthe patient. Additionally or alternatively, controller 30 can be coupledto nebule identification sensor 34 to identify the type of liquid thatis disposed in nebule 28 by reading an identification marker that isprovided on nebule 28. Controller 30 can take the information from flowsensor 32 and/or nebule sensor 34 and run the information through analgorithm to determine an efficient sequence of aerosolization.Typically, the controller will run a selected pre-programmed delivery orsequence program that is stored in controller 30 so as to deliver theaerosol to the patient in an optimal time of the patient's breathingcycle.

Controller 30 can include a memory and a microprocessor so as to storeand run the algorithm that selects the pre-programmed drug deliverysequence. The memory of the controller can store a list or library ofcodes and/or drugs that are compatible with the aerosol generator,information about the drugs, such as a regime to be followed based onthe particular drug, the time in the breathing cycle when the drug isbest administered, the amount of the drug to be aerosolized, or thelike.

Controller 30 will typically be in communication with at least onesensor. As noted above, one sensor can be a nebule identification sensor34 that reads an identification marker on the nebule to identify thetype of liquid disposed within the nebule. The sensor can be amechanical sensor, an electromechanical sensor, an electrical sensor, anoptical sensor or the like. Such sensors can be used to provideinformation to the controller for a number of purposes. For example, theidentification information can be used to identify the type of drug soas to choose the delivery sequence program. Moreover, the identificationinformation can be used as a quality control mechanism to prevent theaerosolization of an incompatible, unsafe, or unknown drug, and thelike.

Another type of sensor that can be coupled to controller 30 is abreathing characteristic sensor 32 that can monitor the breathingcharacteristics of the user. The sensor can send breathingcharacteristic information to the controller to allow the controller toselect an appropriate delivery cycle of the aerosolized liquid to thepatient. Typically, breathing characteristic sensor 32 can be used tomeasure a breathing pattern of the patient, the peak flow, breathingrate, exhalation parameters, regularity of breathing, and the like. Suchmeasured breathing characteristics can be delivered to controller 30 andrun through a software algorithm to determine an appropriate sequence ofdelivery relative to the measured breathing cycle to the patient. Oneexemplary breathing characteristic that may be sensed by sensor 32 isthe cycle of a ventilator providing air to a patient; for example, thestart of an inhalation cycle generated by the ventilator. The sensor 32may sense other parameters, for example, it may be an acoustic sensorthat is activated through passing the respiratory flow of the patientthrough an acoustic chamber (not shown) so as to produce an acoustictone, which is proportional to the inspiratory flow rate. The frequencyof the acoustic tone indicates the inspiratory flow rate at any instantof the breathing cycle. The acoustic signal can be detected by thecontroller such that integration of the flow rate with time produces thetidal volume. Both the flow rate and the tidal volume can then be usedby the controller to determine when the aerosol generator generates thedroplets and at what mass flow rate such that maximum deposition ofdroplets is obtained. Further, the acoustic tone may be recorded toproduce a record of the breathing pattern of the patient which may bestored in the microprocessor. This information can be later used tosynchronize the ejection of droplets for the same patient. Suchinformation may also be later employed for other diagnostic purposes. Amore complete description of such a sensor is described in commonlyowned, U.S. Pat. No. 5,758,637, which was previously incorporated byreference.

In some embodiments, the sensor can be used to monitor the breathingcharacteristics of the patient throughout the delivery regime so as toensure that the aerosol is efficiently delivered throughout theaerosolization procedure. In such embodiments, the controller can adjustthe aerosol delivery based on any measured change in the breathingpattern of the patient during the aerosolization. With this monitoringand adjustment predetermined times for the beginning and ending ofaerosolization can be reset based on the actual breathing of the patent.In other embodiments, however, the breathing sensor can be used todetermine the breathing cycle of a tidal breath and to choose theappropriate pre-programmed delivery cycle that is stored in the memoryof the controller. In other embodiments, the controller may beconfigured to provide aerosol based on the time. For example, thecontroller may be configured to start aerosol production at thebeginning of an inhalation phase of a breathing cycle and stop at apoint at which a predetermined percentage of the inhalation has takenplace. Alternatively, the controller may be configured to startaerosolization at a first point at which a first predeterminedpercentage has taken place and stop aerosolization at a second point atwhich a second predetermined percentage of that inhalation has takenplace. Alternatively, aerosol may begin during an inhalation phase andend during the subsequent exhalation phase. Alternatively, thecontroller may be configured to begin aerosol production at a certainpoint during exhalation and stop during that exhalation or during thesubsequent inhalation. Thus, an aspect of the present invention mayinclude a nebulizer comprising: an aerosol generator and a controllerconfigured to have the controller begin aerosolization during exhalationand stop during that exhalation or in the subsequent inhalation. Inaddition, the controller may be operable to allow for a choice of modesof operation, for example, a mode in which aerosolization begins once acertain breath characteristic is detected, such as a sufficient level ofinhalation, and ends when there is no longer a sufficient level; anothermode in which aerosolization begins once a certain breath characteristicis detected, such as a sufficient level of inhalation, and ends at apredetermined time within the inhalation cycle, such as for example,before the level of inhalation falls below that required for operationof an aerosolization element, or, alternatively, at any other pointwithin the inhalation cycle, such as after the inhalation phase of thecycle before exhalation has begun, or after exhalation has begun.

The level of inhalation may be sensed by a pressure transducer. Such atransducer may monitor a drop in air pressure or a rise in air pressurewithin a chamber that is in fluid communication with the ventilatorcircuit. In this manner, a pressure drop may be sensed by a patientinhaling through the circuit, for example, in an instance in which theventilator provides an assisted ventilation initiated by a patient'scommencement of an inhalation. Similarly, a pressure rise may be sensedin an instance in which the ventilator pushes inhalation air to thepatient without the patient initiating a breath. Another mode in whichthe controller may be operable is a mode in which the on/off operationof the aerosol generator is triggered by time, which may be ascertainedfrom an internal clock device, such as a clock built into amicroprocessor, or from an external source. Another mode in which thecontroller may be operable is in which the on/off operation of theaerosol is triggered by the controller receiving an external signal,such as a signal from a ventilator, which can correspond to the point inthe ventilator's cycle of that is the start of an inhalation phase inwhich the ventilator begins to push inspiratory air into the ventilatorcircuit. The controller may be operable between such modes, including amode in which the aerosolization begins at a predetermined time in thebreathing cycle and ends at a predetermined time in the breathing cycle.The first and second predetermined times in the third mode may be duringinhalation. Alternatively, the first and second predetermined times maybe during exhalation, or at the first predetermined time may be duringexhalation and the second predetermined time may be during subsequentinhalation. These times may correspond to certain percentages of theinhalation phase taking place, or any other points of reference within abreathing cycle.

Alternatively, the first predetermined time and the second predeterminedtime may be designated as any point within a single breathing cycle, oralternatively, the first predetermined point may be at any point withinone breathing cycle and the second predetermined point may be at anypoint in a subsequent breathing cycle. The controller may make thedetermination of when to begin, and operate to begin aerosolization, andmay make the determination of when to stop aerosolization to stop, andcause aerosolization to stop. The controller may make suchdeterminations and take such actions based on accessing storedalgorithms. The controller may receive a signal from the ventilator thatestablishes a reference point, nonetheless, the controller, by makingthe determinations an taking the actions based on stored algorithms,and/or information obtained as to the identity of a drug to beadministered, may cause aerosol production to begin and/or endindependent of the instantaneous position of the ventilator with respectto the ventilator cycle.

The controller may be operable to allow for a single mode of operation,and such single mode of operation may be any mode, for example, asdescribed above. For example, a mode in which aerosolization begins oncea certain breath characteristic is detected, such as a sufficient levelof inhalation, and ends when there is no longer a sufficient level.Similarly, the controller may operable in a mode in which aerosolizationbegins once a certain breath characteristic is detected, such as asufficient level of inhalation, and ends at a predetermined time withinthe inhalation before there is no longer a sufficient level or anaerosolization element.

Alternatively, the mode may be a mode in which the aerosolization iscommenced based on a signal from the ventilator indicating theattainment of a certain point within the ventilation output cycle or theinhalation cycle of the patient. (The ventilation output cycle of theventilator may coincide with the inhalation cycle of the patient, suchthat the ventilation output phase of the ventilator output cycle and theinhalation phase of the inspiratory cycle of the patient occursubstantially simultaneously. Such may be the case where a patient iscompletely passive and the only inhalation that occurs is by generationof air from the ventilator during the output phase of the ventilatorcycle.). Such point may be during the output phase of the output cycleof the ventilator or during the inhalation phase of the inhalation cycleof the patient. The predetermined point can be chosen to coincide with acertain level of output from the ventilator or at a certain point intime during the ventilator output cycle. Such a predetermined point maybe a specific point within the output phase of the ventilator cycle, or,a specific point within the non-output phase of the ventilator cycle,based, for example, on the timing of the previous or succeeding outputphase of the ventilator. In another aspect, the present inventionprovides for a ventilator along with the aerosol generator andcontroller. In an aspect of the invention, a predetermined time may bebased on the timing of a ventilator supplying air to a user. In thismanner, the controller may be set to work off of the timing of theventilator in one mode, while working off the patient's inspiratoryeffort in another mode, or mode that allows for a combination of thepatient's inspiratory effort and the timing of the ventilator, forexample, where the ventilator is set to assist the patient by supplyingair upon the patient's effort or where the patient has not made asufficient effort within a predetermined period of time.

In regard to the aerosol generators 22 of the present invention, theymay be of the type, for example, where a vibratable member is vibratedat ultrasonic frequencies to produce liquid droplets. Some specific,non-limiting examples of technologies for producing fine liquid dropletsis by supplying liquid to an aperture plate having a plurality oftapered apertures and vibrating the aperture plate to eject liquiddroplets through the apertures. Such techniques are described generallyin U.S. Pat. Nos. 5,164,740; 5,938,117; 5,586,550; 5,758,637, 6,014,970,and 6,085,740, the complete disclosures of which are incorporated byreference. However, it should be appreciated that the present inventionis not limited for use only with such devices.

FIGS. 2 to 10 illustrate some exemplary feed system interfaces 26 andnebules 28 of the present invention. As shown in FIG. 2, nebule 28 canbe an ampoule that comprises a body 36 with a top end 38 and a bottomend 40. Bottom end 40 can include a tapered opening that can deliver theliquid from ampoule 28 into a fluid reservoir 42 adjacent aerosolgenerator 22. Top end 38 can include a twist-off vent 44 that can beremoved to create a drain vent in top end 38. Some exemplary ampoulesthat can be used with the present invention are described in co-pendingU.S. patent application Ser. No. 09/812,755, filed Mar. 20, 2001, thecomplete disclosure of which was previously incorporated by reference.

The ampoules of the invention may be used to store a wide variety ofliquids. Merely by way of example, liquids that may be stored within theampoules include various pharmaceuticals such as saline, albuterol,chromatin, budesinide, nicotine, THC, cocaine, antibodies, such as IgG,antibodies, such as aminoglycosides, and the like. Other liquids thatmay be stored include insecticides, deodorizers, perfumes, and the like.Hence, it will be appreciated that the ampoules of the invention may beused to store essentially any type of liquid that is capable of beingaerosolized.

The ampoules of the invention may be constructed by blowing orvacuum-forming the ampoule in a mold, filling the ampoule with liquid,and melt-sealing the liquid into the ampoule. The ampoules may furtherbe provided with a set of removable tabs to provide a drain vent and adrain opening. Typically, these will be located in the top and bottom ofthe ampoule so that the liquid may drain by force of gravity once theopenings are formed. The tabs may be removed by twisting, cracking, orthe like so that the opening may be formed. In some cases, the ampoulesmay be configured to be opened simply by piercing the top and/or bottomend. Such piercing elements may conveniently be incorporated into theaerosolization device.

Various materials may be used to construct the ampoules, such asmoderate durometer polymer materials, thermoplastic synthetics, such aslow density polyethylene and polypropylene, and the like. The ampoulesmay be provided with a thick enough wall to minimize droplet spillage.For instance, the wall thickness may be greater than about 0.030 inch.The ampoule may further be configured so that the diameter of the drainopening minimizes the drip potential for the fluid stored within theampoule. For example, larger diameter openings may be provided whenstoring higher viscosity fluids and smaller diameter openings may beused for low viscosity fluids.

The ampoules of the present invention can include a connection or keyingelement 46, such as a thread or a tab so as to accurately align theampoule 28 with a nebulizer feed system interface 26. The feed systeminterface 26 will have a corresponding feature or slot 48 to engage theconnection element. In the exemplary embodiment illustrated in FIGS. 2to 4, ampoule 28 can include a helical keying element 46 that is shapedto mate with the corresponding keying feature 48 in feed system 26. Toinsert the ampoule into feed the system, the ampoule is moved axially(in the direction of arrow 50) until helical keying element 46 ispositioned adjacent the corresponding keying feature 48. Thereafter, theampoule 28 is rotated to mate the keying element 46 and the keyingfeature 48 together so as to pull the ampoule 28 axially downward untilthe bottom end 40 of the ampoule 28 opens slit seal membrane 52 in feedsystem 26 (FIGS. 3 and 4).

In the exemplary embodiments, ampoule 28 includes an identificationmarker 35 to identify to the controller, the liquid that is withinampoule 28. Identification marker 35 can be a bar code (e.g., embossedor printed), one or more bumps or protrusions, a radio frequencyidentifier, a small chip containing stored information, or othersuitable identification technology. In the embodiments depicted in FIGS.2 to 4, information regarding the contents of the ampoule is conveyedthrough a series of protrusion identification markers 35 on the ampoule28 that are sensed by their interaction with an optical detector 56during the rotational engagement of ampoule 28 with the feed systeminterface 26. In this particular embodiment, a miniature light source 58and the optical sensor 56 are coupled to the feed system 26 such that apassing protrusion 35 affects the sensed light in a manner such that thesensor 56 may provide information (e.g., typically binary information,i.e., a “0” or a “1”) based on position, number, or absence of theprotrusion. Thus, rotation of an ampoule 28 as it is threadedly insertedinto the nebulizer feed system 26 may count the number of bumps orprovide a code such as “1-0-1-0” so as to inform the nebulizercontroller 30 (FIG. 1) the type of medicant or other liquid that isdisposed in the ampoule. A single sensor can read the code imparted by aseries of protrusions as the ampoule 28 is moved axially into thenebulizer feed system 26 while it is rotated through the threadedfeatures in the housing of feed system 26.

FIG. 5 illustrates another exemplary nebule identification sensor 34 andampoule 28. Nebule sensor 34 can include an electromechanical switchthat contacts the protrusions on the nebule as it is inserted into thefeed system. As shown in FIG. 5, the nebule includes a helical keyingelement 46 that interacts with a corresponding helical keying feature(not shown) to position the ampoule within feed system interface 26. Asthe ampoule is rotated and moved axially downward, the protrusionidentification markers will contact and actuate a metal spring-likecontact 60 of nebule sensor 34 so as to create a circuit and send anidentification electrical signal to controller 30 to identify the typeof drug in ampoule 28. As shown in the plan view of FIG. 6, nebulesensor 34 can include one or more metal contacts 60, such that rotationof the ampoule 28 can cause the protrusion identification markers tocontact the metal contacts 60, 60′. By changing the spacing and numberof protrusion identification markers, a unique electrical identificationsignal can be generated to identify the liquid in the ampoule to thecontroller. In turn, the controller can then select and run a deliveryprogram that provides an efficient delivery of the identified liquid.

Another exemplary ampoule 28 and feed system interface 26 is illustratedin FIGS. 7 and 8. As shown in FIG. 7, an ampoule bottom end 40 having akeying tab 46 can interact with a spiral slot 48 in the feed systeminterface 26. As the ampoule is inserted and rotated within the feedsystem interface 26, the keying element(s) engage the spiral slot 48 soas to pull the ampoule down into the interface (FIG. 8). Similar to theabove embodiments, the bottom end of the ampoule can protrude throughslit seal membrane 52 so as to be able to deliver the liquid toreservoir 42. Identification markers 35 can be sensed by theidentification sensors (not shown), as described in the aboveembodiments.

The ampoule protrusion identification markers 35 can be in a singlehelix configuration or a double helix configuration. In exemplaryembodiments, the identification markers are in a double helixarrangement so that as the first set of protrusions is read, providing abinary code to the system, the second set of protrusions can provide acomplementary binary code (read by a second optical detector, not shown)as ampoule 28 is screwed into nebulizer feed system 26 (FIGS. 2 to 4).Thus, the binary code of the first series of protrusions might, forexample, convey the code “1-0-1-0” as each of protrusions are sensed asthe ampoule is screwed into the nebulizer feed system housing, while thesecond series provides the complementary code of “0-1-0-1”. In thismanner, the controller can check that when a particular binary code istransmitted by the first set of protrusions, the complementary binarycode is sensed by the second set of protrusions. Thus, the system canprevent the potential mis-information that might be transmitted werethere only a single set of protrusions provided to convey theinformation, and the insertion was done incorrectly.

Such interaction further allows the system to check against a situationin which one or more ampoule protrusions are damaged to the extent ofeffecting the sensing function, because the system will have the codeprovided by the second series of protrusions to check against theinformation provided by the first set of protrusions.

Alternatively, the second set of protrusions may be used to provide morecode combinations for different drugs. In exemplary embodiments, byproviding three bumps or protrusions on each side of the ampoule, thecontroller of the aerosol generator can determine which of 9 drugs ormedicants are disposed in the ampoule. For example, the followingdistribution of bumps or protrusion can deliver a signal to thecontroller to indicate the identity of the following drugs:

Drug Type Number of Bumps on Side 1 Number of Bumps on Side 2 Drug A 1 0Drug B 2 0 Drug C 3 0 Drug D 1 1 Drug E 2 1 Drug F 3 1 Drug G 2 2 Drug H2 3 Drug I 3 3

In the embodiment illustrated in FIGS. 2 to 8, the protrusionidentification markers 35 are disposed in a helical configuration thathas a pitch that substantially matches the pitch of the helical keyingelement 46, such that as the helical keying element is rotated and movedthrough the corresponding keying feature 48, the protrusionidentification markers pass by the optical sensor 56 or metal contacts60. It should be appreciated however, that the identification markers 35can be disposed in a variety of non-helical patterns, as will bedescribed in relation to FIGS. 9 to 10.

FIG. 9 illustrates one exemplary embodiment of an ampoule 28 havingidentification markers 35 that are disposed in a non-helicalarrangement. As illustrated, ampoule includes a keying slot 62 adjacenta bottom end of ampoule 28 to allow the ampoule to be inserted into feedsystem interface 26. If keying slot 62 does not correspond with thekeying tab 64 on the interface, the ampoule will be prevented from beingseated within the interface and the liquid in the ampoule will beprevented from being delivered to reservoir 42. In situations where thekeying slot matches the keying tab, as ampoule 28 is inserted axiallyinto feed system and twisted to engage the keying slots with the keyingtabs, the identification marker 35 will simultaneously pass acrossnebule sensor 34. The illustrated embodiment includes a bar code readerthat reads a bar code identification marker, but it should beappreciated that the identification marker 35 and identification sensor34 can include any of the other types of identification markers andsensors or their equivalents, as described above.

FIG. 10 illustrates an ampoule 28 that includes bump identificationmarkers that are disposed on the ampoule such that axial insertion ofthe ampoule (without rotation) into the feed system interface 26contacts the bump identification markers 35 against theelectromechanical contacts 60. Ampoule 28 can include a retainer orclick positive position feedback element 66, and/or alignment means foraligning the ampoule into the feed system.

Variations to the above description may be made in accordance with thepresent invention. For example, ampoule 28 can include other keyingelements and/or orientation elements to ensure that the ampoule isproperly oriented when it is inserted into the aerosolization device. Amore detailed description of such keying elements and orientationelements can be found in co-pending U.S. patent application Ser. No.09/812,755, filed Mar. 20, 2001, the complete disclosure of which waspreviously incorporated herein by reference. In such embodiments, theidentification markers 35 can be disposed on the ampoule relative tosuch keying or orientation elements in any position in which the sensorscan sense the markers and determine the type of medicament or drug thatis disposed in the ampoule.

Methods of the present invention will now be described. In one method,the present invention identifies the contents of the nebule to improvethe operation of the aerosol generator. As illustrated in FIG. 11, anaerosol generator is provided (Step 100) and a nebule is coupled to anebule interface of the aerosol generator (Step 102). An identificationmarker on the nebule is read by the aerosol generator (Step 104) and theaerosol generator is operated according to an operation program based onthe information read from the identification marker on the nebule (Step106).

Typically, the aerosol generator is operated with a controller (FIG. 1).The controller typically includes a memory that stores a plurality ofoperation programs for delivering each of the compatible specific typesof drugs or medication. After the identification marker is read by asensor, the information is passed to the controller so that a correctoperation program can be selected to operate the aerosol generator. Theoperation program can control the start and stop times of the aerosolgenerator, the aerosol production rate, the amplitude of vibration ofthe aerosolization element, the frequency of aerosolization, and thelike.

It should be appreciated that, in addition to using the identificationmarker information to control the operation of the aerosol generator,the information from the identification marker may be used for otherpurposes. For example, as shown in FIG. 1, the systems of the presentinvention 20 may optionally include an output device 68, such as aprinter, audio speaker, or LCD. When the identification informationreceived by the sensor matches a code entry inside the controllermemory, the drug name, dosage information, or other pertinentinformation can be made available to the user by displaying orannouncing the information via the attached output devices.Additionally, the identification markers can be used for preventing thewrong drug from being administered to the patient by setting the aerosolgenerator controller to operate the aerosol generator only on thereception and identification of one or more particular drugcodes/identification markers to the exclusion of others: e.g. onepatient's nebulizer may be set to accept nebules containing, and codedfor, drug A and drug B, while another patient's nebulizer may be set toonly operate if a nebule contains, and is coded for, drug A.

Typically, the identification marker is positioned adjacent a sensorthrough use of a keying element on the nebule. The keying elements caninteract with a corresponding keying feature on the aerosol generatorinterface to position the identification marker adjacent the sensor. Inother methods, however, the keying elements on the nebule can be used tocontrol the types of nebules that can be coupled to the aerosolgenerator system. In such methods, as shown in FIG. 12, a nebulizersystem and a nebule comprising a nebule body with a keying element(e.g., threads, tabs, slots, and the like) are provided (Steps 110,112). The nebule can be inserted into the housing. If the keying elementis properly keyed with a housing of the nebulizer system, the nebule canaccess a reservoir of the system (Step 114). Thereafter, the liquid fromthe nebule will be transferred into the reservoir for aerosolization(Step 116). The aerosol generator can then be operated with a controllerto aerosolize the liquid (Step 118).

The keying elements, identification markers, or both can be used toensure that only nebules which are compatible with the feed system andaerosol generator are used. For example, as a first precaution, theaerosol generator systems of the present invention can include a keyingfeature that mates only with certain types of nebules. For example,nebules containing steroids may have a different keying element thannebules containing antibiotics. Therefore, patients using the aerosolgenerator only for steroidal delivery will be prevented from keying thenebule containing an antibiotic to the aerosol generator andinadvertently nebulizing the antibiotic, and vice versa.

Additionally or alternatively, the controller of each individual systemcan be programmed to only have available sequence delivery programs(which may be referred to as operation sequences, or algorithms foroperation sequences) for selected medicants or drugs that are found in alibrary of codes and drugs in the controller memory. Thus, if theidentification marker on a nebule that is coupled to the aerosolgenerator is not one of the drugs on the list stored in the controllermemory, the controller will not deliver the aerosol to the patient.Optionally, the controller can provide an output informing the user thatthe installed nebule is incompatible with the system.

In other exemplary methods, the present invention can measure thecharacteristics of a persons inhaled breath, typically a tidal breath,to control the operation of the aerosol generator. As shown in FIG. 13,a person can take one or more breaths (Step 120) and the characteristicsof the breath can be measured (Step 122). The breathing characteristicsthat can be measured include, but are not limited to, a breathingpattern, peak inspiratory flow rate, breathing rate, exhalationparameters, regularity of breathing, tidal volume, and the like and canestimate a user's tidal volume based on such information. The user cantake another tidal breath and the aerosol generator can be operatedbased on the measured characteristics of the tidal breath (Step 124). Itshould be appreciated however, that instead of a tidal breath, theperson can take other types of breath. Alternatively, the controller maybase the timing of operation of the aerosol generator so that aerosol isgenerated at specific time periods within a breathing cycle, (Step 125,FIG. 13 a). For example, the controller may operate the aerosolgenerator for the first 50 percent of inspiration. Alternatively, thecontroller may operate the aerosol generator to generate aerosol after aportion of inhalation has taken place and to cease producing aerosolafter another portion of inhalation has taken place. For example, thecontroller may cause aerosol to be generated beginning after 20% of theinspiration has taken place and cause aerosol production to cease after70% of inspiration has taken place. The controller may cause aerosolproduction to start after, for example, after 90% of exhalation hastaken place and, for example, cause aerosol production to stop after 30%of the following inspiration has taken place. By controlling thespecific timing within the breathing cycle that aerosolized medicationis provided into the breathing circuit, greater efficiency of drugadministration can be achieved. With reference to FIGS. 15 a-15 c, forexample, continuous aerosolization may yield only about 10% to about 15%efficiency (FIG. 15 a), aerosolization during the entire inhalationphase of the breathing cycle may yield about 15% to about 25% efficiency(FIG. 15 b), and delivery during a predetermined portion of theinhalation phase beginning, for example, at the onset of inhalation, mayprovide a drug yield between about 60% to about 80% efficacy (FIG. 15c). Accordingly, the present invention, by controlling delivery to apredetermined percentage of the breathing cycle, such as a predeterminedpercentage of the inhalation phase of the breathing cycle, provides fargreater efficiency than either continuous delivery or delivery duringthe entire inhalation phase. Further, and surprisingly, the percentageof increase in efficiency in delivery for such a predetermined portionof the inhalation phase (FIG. 15 c) over delivery during the entireinhalation phase (FIG. 15 b) is itself far greater than the increase inefficiency of delivery during the inhalation phase (FIG. 15 b) oversimply continuously providing aerosol (FIG. 15 a).

By utilizing an aerosol generator that produces aerosol by the electricpowering a vibratable member that causes an aperture plate to ejectliquid at one face thereof, through its apertures, as a mist from theother face thereof, as generally described above (and as describedgenerally in U.S. Pat. Nos. 5,164,740; 5,938,117; 5,586,550; 5,758,637,6,085,740; and 6,235,177, the complete disclosures of which are, andhave been above, incorporated herein by reference), the starting andstopping of aerosol generation may be controlled on the level ofaccuracy of microseconds or milliseconds, thus providing accuratedosing. The timing of aerosol generation can be done based solely on apredetermined timing within a breathing cycle, on timing in conjunctionwith the length of a prior breath or portions thereof, on otherbreathing characteristics, on particular medication being administered,or a combination of any of these criteria (Step 135, FIG. 13 b).

The aerosolization element may be constructed of a variety of materials,comprising metals, which may be electroformed to create apertures as theelement is formed, as described, for example, in U.S. Pat. No. 6,235,177assigned to the present assignee and incorporated by reference herein inits entirety. Palladium is believed to be of particular usefulness inproducing an electroformed, multi-apertured aerosolization element, aswell as in operation thereof to aerosolize liquids. Other metals thatcan be used are palladium alloys, such as PdNi, with, for example, 80percent palladium and 20% nickel. Other metals and materials may be usedwithout departing from the present invention. The aerosolization element70 (referring now to FIGS. 16 a and 16 b) may be configured to have acurvature, as in a dome shape, which may be spherical, parabolic or anyother curvature. The aerosolization element may be formed to have a domeportion 73 over its majority, and this may be concentric with the centerof the aerosolization element, thus leaving a portion of theaerosolization element that is a substantially planar peripheral ringportion 75. The aerosolization element has a first face 71, a secondface 72 and a plurality of apertures 74 (FIG. 16 b) therethrough. Thefirst face 71 may comprise the concave side of the dome portion 72 andthe second face 72 may comprise the convex side of the dome portion 72of the aerosolization element 70. The apertures may be tapered to have anarrow portion 76 at the first face 71 and a wide portion 78 at thesecond face 72 of the aerosolization element 70. Typically, a liquidwill be placed at the first face of the aerosolization element, where itcan be drawn into the narrow portion 76 of the apertures 74 and emittedas an aerosolized mist or cloud 79 from the wide portion 78 of theapertures 74 at the second face 72 of the aerosolization element 70.

The aerosolization element may be mounted on an aerosol actuator 80,which defines an aperture 81 therethrough. This may be done in such amanner that the dome portion of the aerosolization element protrudesthrough the aperture 81 of the aerosol actuator 80 and the substantiallyplanar peripheral ring portion 74, on the second face 72 of theaerosolization element 70 abuts a first face 82 of the aerosol actuator80. A vibratory element 84 may be provided, and may be mounted on thefirst face 82 of the aerosol actuator 80, or alternatively may bemounted on an opposing second face 83 of the aerosol actuator 80. Theaerosolization element may be vibrated in such a manner as to drawliquid through the apertures 74 of the aerosolization element 70 fromthe first face to the second face, where the liquid is expelled from theapertures as a nebulized mist. The aerosolization element may bevibrated by a vibratory element 84, which may be a piezoelectricelement. The vibratory element may be mounted to the aerosol actuator,such that vibration of the vibratory element may be mechanicallytransferred through the aerosol actuator to the aerosolization element.The vibratory element may be annular, and may surround the aperture ofthe aerosol actuator, for example, in a coaxial arrangement. In someembodiments of the present invention, the aerosolization element or theaerosol generator comprising the aerosolization element 70, the aerosolactuator 80 and the vibratory element 86 may be replaced with arespective assembly that has apertures of a different size, such as adifferent exit diameter, to produce a mist having a different aerosolparticle size. A circuitry 86 may provide power from a power source. Thecircuitry may include a switch that may be operable to vibrate thevibratory element and thus the aerosolization element, andaerosolization performed in this manner may be achieved withinmilliseconds of operation of the switch. The circuitry may include acontroller 87, for example, a microprocessor that can provide power tothe vibratory element 84 to produce aerosol from the aerosolizationelement 70 within milliseconds or fractions of milliseconds of a signalto do so. For example, aerosol production may begin within about 0.02 toabout 50 milliseconds of such a signal and may stop within about 0.02 toabout 50 milliseconds from the cessation of a first signal or a secondsignal either of which may act as a trigger to turn of aerosolization.Similarly, aerosol production may begin and end within about 0.02milliseconds to about 20 milliseconds of such respective signaling.Likewise, aerosol production may begin and end within about 0.02milliseconds to about 2 milliseconds of such respective signaling.Further, this manner of aerosolization provides full aerosolization witha substantially uniform particle size of low velocity mist 79 beingproduced effectively instantaneously with operation of the switch.

With reference to FIG. 17, a nebulizer 85, which may have a top portion93 through which liquid (either directly or within a nebule) may beprovided, in accordance with the present invention may be incorporatedinto a ventilator breathing circuit of a ventilated patient. Thebreathing circuit may comprise a “Y” connector 88, which may in turnhave an inlet portion 89, an endotracheal tube portion 90 and an outletportion 91. The inlet portion 89 carries air provided from theventilator 92 toward the patient. The endotracheal tube portion 90 ofthe Y connector 88 carries the incoming air to the patient's respiratorytract; this direction is represented by arrow a. The endotracheal tubeportion 90 also carries the patient's exhalation to the outlet portion91 of the Y connector 88, and the outlet portion may lead to an exhaust,represented by arrow b, to remove the patient's exhalation from thesystem. The nebulizer 85 of the present invention aerosolization elementgenerates an aerosol cloud 94 that remains substantially within theinlet portion 89 of the Y connector 88 when there is no inspiratory airflowing through the inlet portion, by virtue of the aerosolizationelement, as described above, producing a low velocity mist. In thismanner, aerosol that is generated when there is no inhalation air beingprovided will not be carried out through the outlet portion 91 of the Yconnector and lost to the ambient environment. Accordingly, a dose ofaerosolized medication may be preloaded, i.e., produced and placedsubstantially within the inlet portion 89 prior to an inhalation phasebeing sent by the ventilator 92. In this manner, such medication can beswept into a patient's respiratory system at the very start of theinhalation cycle. This may be of particular benefit in the case ofneonatal patients and in other instances in which only the initial blastof inhalation phase will reach the target portion of the respiratorysystem.

The switch, described above, may be operable by a pressure transducer,which may be positioned in the mouthpiece of the nebulizer. The pressuretransducer may be in electrical communication with the circuitry, and amicroprocessor may also be in electrical communication with thecircuitry, and the microprocessor may interpret electrical signals fromthe pressure transducer, and may also operate the switch to beginaerosolization. In this manner, nebulization can begin substantiallyinstantaneously with the inhalation of a user upon the mouthpiece. Anexample of such a sensor switch can be found in co-assigned andco-pending U.S. application Ser. No. 09/705,063 assigned to the presentassignee, the entire content of which is hereby incorporated herein byreference.

Another transducer may be used to sense the absence or presence ofliquid in the reservoir, by sensing, for example, a difference betweenvibration characteristics of the aerosolization element, such as, forexample, differences in frequency or amplitude, between wet vibrationand substantially dry vibration. In this manner, the circuitry, may, forexample by way of the microprocessor, turn the vibration off when thereis essentially no more liquid to aerosolize, i.e., when the end of thedose has been achieved, thus minimizing operation of the aerosolizationelement in a dry state. Likewise, the switch may prevent vibration priorto delivery of a subsequent dose into the reservoir. An example of sucha switch is shown in co-assigned and co-pending U.S. application Ser.No. 09/805,498, the entire content of which is hereby incorporatedherein by reference.

As shown schematically in FIG. 14, in exemplary embodiments, the aerosolgenerator controllers of the present invention can be coupled to both anebule identification sensor and a breathing characteristic sensor so asto identify the liquid that is delivered to the aerosol generator and tomonitor the breathing characteristics of the patient (Steps 130 to 140).In such embodiments, the aerosol generator can be operated (and apre-programmed delivery program can be selected) to run the aerosolgenerator, based at least in part on the information obtained from theidentification sensor and breathing characteristic sensor (Step 140).

If it is known what type of medication or drug is being delivered, thecontroller can select the best time during the patient's breathing cycleto deliver the aerosol, based upon a predetermined regimen for that drugthat is stored in memory. As an additional benefit, an estimate of thepatient's age and/or distress can be made, for example, by measuring thetidal volume and breathing rate. Such measurements can influence theefficiency requirements of the dose per breath. These or other variablescan be used in establishing various regimes for aerosol delivery, inparticular delivery into the breathing circuit of a ventilator. Theseregimes can be stored in memory and then accessed by the controller asappropriate for a given patient condition.

For example, for a bronchodilator the best time to delivery may be halfway through the inhalation phase of a breath when impaction would bereduced since inhalation flows are reducing. For steroids, it may bebest to deliver towards the end of the inhalation phase of a breath. Forantibiotics, it may be best to slightly pre-load, i.e. deliver aerosolduring the exhalation phase, or deliver right at the start of thebreath. For example, antibiotics may be delivered at the beginning of aventilator provided inhalation, and the aerosol delivery may stop aftera predetermined percentage of the inhalation has been provided. Oneclass of antibiotics that may be administered in accordance with thepresent invention is the class known as the aminoglycoside class ofantibiotics. This class of antibiotics has typically been administeredintravenously, however, such delivery may have unwanted side effects,which may be systemic. An object of the present invention is theadministration of antibiotics, such as aminoglycosides includingamikacin by delivering it in aerosolized form into the breathing circuitof a patient on a ventilator. In this manner, amikacin can be used totreat pulmonary infection conditions that typically arise when patientsare mechanically ventilated, and the amikacin, or other aminoglycosideor other antibiotic, can be delivered directly to the target oftreatment, the pulmonary tract, avoiding side effects that may otherwisearise from intravenous administration. Further, because of the greatcost of such drugs, far greater efficiency is achieved through thispulmonary delivery. As noted above, with reference to FIG. 15 c,delivery of aerosol during a beginning percentage of the inhalationphase of a breathing cycle may yield up between about 60% and about 80%efficiency, an this is significantly higher than efficacy of continuousaerosolization or aerosolization for an entire inhalation phase of aninhalation cycle.

As described above, various regimes of aerosolization can be followed,depending on the situation. For example, in FIG. 18, a selection betweena first, second and third regime is shown. A regime may be selectedmanually or automatically, for example, through the application of analgorithm that selects an operation program based on information that iseither input or stored. For manual selection, a user may operate amechanical switch to select a regime, or may enter such a selection intoan electronic input device, such as a keyboard. Alternatively, thecontroller may automatically choose a regimen, as described above, bymatching a drug code on a drug nebule with a library of drug-regimencombinations. (It should be noted that in FIGS. 18, 19 and 20, schematicflow charts of operation sequence algorithms are depicted. Althoughitems therein will be referred to as steps for ease of discussion, theyrefer more broadly herein to states of operations or modalities in whicha system may exist or cycle through. Steps depicted in a rectangle areessentially states of operation, actions or modalities. Steps depictedin diamonds indicate either a selection or the continuance of theprevious state of operation, action or modality until a predeterminedcondition is satisfied. Two successive diamonds refer to satisfaction ofa first condition and of a second condition respectively, the second ofwhich may be a subset of the first.)

In step 200, a choice is made to follow a particular regime. In thiscase, regime I is a regime in which aerosol is generated continuously(step 202). Regime II provides aerosol generation during the inhalationphase only (step 204). In this case, in step 206, aerosol generation isset to start at the start of the inhalation phase and, in step 208,aerosol generation is set to stop when the inhalation phase stops. Instep 210, aerosol generation begins at the start of the inhalationphase. In step 212, when the inhalation phase ends, aerosol generationstops (step 214).

Regime III provides for inhalation during a predetermined percentage ofthe inhalation phase (step 216). A predetermined percentage of aninhalation (or exhalation) phase may be based on a measured time from adiscrete point in the ventilator cycle, such as the instantaneouscommencement of inspiratory air generation by the ventilator.Alternatively, such predetermined percentage may be based on the timeinterval between successive discrete points in the ventilator, such assuccessive commencements of successive inhalation air generation by theventilator. Alternatively, such percentages may be based upon airpressure in the ventilator circuit, or any other parameter. With respectto Regime III, in this case, in step 218, a first predetermined point isset to correspond with the completion of a first predetermined percentof the inhalation. In step 220, a second predetermined point is set tocorrespond to a second predetermined percent of inhalation percent beingcompleted. For example, as described above, the first predeterminedpoint may correspond to 20% of the inhalation phase being completed, andthe second predetermined point may correspond to a point at which 70% ofthat same inhalation has taken place. In step 222, aerosol generationbegins at the first predetermined point in the inhalation phase. In step224, when the second predetermined point is reached, the controllercarries out step 214 and stops the aerosol generation.

Similarly, as noted above, other regimes may be followed, for example,in which aerosol generation begins during the inhalation phase and endsduring the exhalation phase, or begins during exhalation and ends duringthat exhalation, or begins during exhalation and ends in the subsequentbreath cycle, for example, at a predetermined point in the subsequentinhalation phase. Accordingly, turning to FIG. 19, a selection may bemade, at step 230, between regimes II (step 232) and III (step 234) asdescribed above, and another regime, regime IV (steps 236-242), which isalso available for selection. In regime IV, aerosol generation may beginat a first predetermined point (step 236), and this first predeterminedpoint may be after a predetermined percentage of the inhalation phasehas taken place, or it may be a predetermined point after the inhalationphase has been completed. For example, this point may be a predeterminedpoint after a predetermined percent of the exhalation phase has takenplace, or may be a predetermined point prior to the start of thesubsequent inhalation phase. Aerosol generation may stop duringexhalation (regime IVa, step 238), at the completion of exhalation(regime IVb, step 240), or aerosol generation may continue into the nextbreath cycle (regime IVc, step 242), and stop, for example, after apredetermined point during the subsequent inhalation phase.

In this example, with the controller having a selection choice betweenoperation sequences corresponding to regimes II, III and IV, schematicrepresentation of the operation sequences are shown in FIG. 20. In step250, a regime is selected. In step 252, the aerosol generator controllerselects an operation sequence based on selected regime. In step 254, thecontroller receives a signal indicating that ventilator has begun tosupply an inhalation phase. The signal, as described above, may be asignal provided directly by the ventilator. Alternatively, the signalmay be provided by a sensor, and such sensor may sense the commencementof an inhalation phase provided by the ventilator, as described above,by sensing a pressure change in the breathing circuit. In step 256, thecontroller carries out selected operation sequence. In the case ofregime II (step 258), the controller turns on aerosol generator uponcommencement of inhalation phase provided by the ventilator. Thecontroller continues to operate the aerosol generator until a point atwhich the inhalation phase completed (step 260). In step 262, controllerturns off aerosol generator.

In the case of regime III, the controller does not take any action tobegin aerosol generation, until a predetermined point in the inhalationphase, corresponding to a percentage of the inhalation phase beingcompleted (step 264). In step 266, at a predetermined point in theinhalation phase, the controller turns on aerosol generator. In step268, aerosol generation continues until a second predetermined pointinhalation phase, corresponding to a second percentage point ofcompletion of the inhalation phase. At this point, the controllercarries out step 262 and turns off aerosol generator. With respect toregime IV, aerosol generation begins after a predetermined point ofcompletion of the inhalation phase (step 264) and this point may bepredetermined to occur after the inhalation phase has been completed andthe exhalation phase has begun (step 270). In step 272, the controllerturns the aerosol generator on to begin aerosolization. Variations canbe made as to the point at which the aerosol generation is turned off.If it is desired that aerosol generation be completed before thecompletion of the exhalation phase (regime IVa), then aerosol generationmay continue until a predetermined point prior to the subsequentinhalation (step 276). Alternatively, it may be desirable to continueaerosolization until the end of exhalation, which may correspond to thepoint of commencement of the subsequent inhalation, as in regime IVb(step278). Alternatively, it may be desired to follow a regimen such asregime IVc, where aerosol generation continues through into thesubsequent breath cycle (step 280), until, for example, a predeterminedpercent of the subsequent inhalation phase has been completed (step282). In these regimes, aerosolization will continue until thesatisfaction of these conditions (step 276 for regime IVa, step 278 forregime IVb or step 282 for regime IVc), at which point the controllercarries out step 262 and stops the aerosol generator. The process maycontinue with the next signal indicating that the ventilator has begunto provide an inhalation phase, step 254.

Further, the choice of which operating sequence to follow may rely atleast in part on the identity of a drug to be administered, whichinformation can be considered by the controller as described above. Inaddition, it should be appreciated that modifications may be made tothese examples without departing from the present invention. Forexample, a system may be configured, or a method may be carried out, tobe able to select more than three initial regimes to follow. Forexample, regimes I, II, III and IV as described above may besimultaneously selectable. Further, various steps may be altered; forexample, some steps may not be discrete steps. Thus, step 256 may not bea discrete step but rather the following of an operation sequenceaccording to a selected regime. Similarly, the order of the steps may bechanged, such as the controller may select an operating sequence (step252) after receiving a signal that the ventilator has commenced toprovide an inhalation phase (step 254). Steps may also be combined, suchas, for example, in regime IV steps 264 and 270 may be combined as asingle step, as these two steps represent successive criteria for thedetermining a single first predetermined point has been met. Likewise,step 274 may be combined with steps 276, 278 or 280, as step 274 is thepredicate for the condition test specified in each of the othersuccessive tests, steps 276, 278 or 280. The algorithm examples may bealtered to form other operating sequences. For example, an operatingsequence may call for the controller to start aerosol generation at thestart of the inhalation cycle provided by the nebulizer, as in regimeII, at step 258, and turn off the aerosol generator at a point at whicha predetermined percentage of the inhalation phase has been completed,as in regime III, step 268 (and step 262). In a similar manner, othercriteria may be used to trigger the turning on or off of the aerosolgenerator. For example, as described above, the start of aerosolizationmay be triggered by the sensing of a particular pressure or change inpressure in the ventilator circuit, and may end by following the tuningoff sequence of regimes III (steps 268 and 262) or IV (steps 274, 276,278 or 280 and 282, followed by step 262, as described above.

FIG. 21 is a schematic representation of an algorithm by which anoperating sequence, for providing nebulized drug to a patient receivingair from a ventilator, may be chosen based on the combination of aplurality of independent sets of information, in this case, drugidentity and a signal from the ventilator. In step 300, a library ofdrug regimes is provided, the library based on various drugs that may beadministered. In step 302, the identity of a particular drug is providedto the system, and this may be provided, as described above, by a markeron a nebule containing the drug, the marker being read by the system. Instep 304, the controller looks up a regime from the library of storedregimes to select a regime based on the particular drug to beadministered. In step 306, the controller receives a signal from theventilator. In step 308, the controller then chooses an operationsequence based in part on the drug identity and drug regime and in parton the independent information provided by the signal from theventilator. In step 310, the controller carries out the operationsequence, which may be producing aerosol at a predetermined interval inthe ventilation cycle based on the drug and the regime provided for thedrug factored in with the inhalation cycle of the ventilator. Thesedescriptions are illustrative, and accordingly, the order of the stepsmay be altered, and other variations, additions and modifications, asdescribed above, may be made still in accordance with the presentinvention.

While all the above is a complete description of the preferredembodiments of the inventions, various alternatives, modifications, andequivalents may be used. Accordingly, although the foregoing inventionhas been described in detail for purposes of clarity of understanding,it will be obvious that certain modifications may be practiced withinthe scope of the appended claims.

1. A method for providing a nebulized fluid to a ventilated patient, themethod comprising: vibrating an aerosolization element in the presenceof a fluid, wherein the aerosolization element includes a plurality ofapertures that nebulize the fluid while the aerosolization element isvibrating; introducing the nebulized fluid into a breathing circuit; andcontrolling vibration of the aerosolization element during a certaininterval of a breathing cycle; wherein the fluid comprises an antibioticthat is selected to treat a pulmonary infection resulting frommechanical ventilation.
 2. The method of claim 1, wherein the intervalis selected based on the antibiotic.
 3. The method of claim 1, whereinthe antibiotic is an aminoglycoside.
 4. The method of claim 3, whereinthe aminoglycoside is amikacin.
 5. The method of claim 1, furthercomprising: providing a tube into which the nebulized fluid isintroduced; and coupling the tube into an existing ventilator linebetween a ventilator and the patient, without necessitating adjustmentof the operation of the ventilator.
 6. The method of claim 1, furthercomprising: sensing at least one characteristic of the patient'sbreathing cycle using a sensor; and recognizing the breathing cycleinterval based on information from the breathing sensor.
 7. The methodof claim 1, wherein vibrating the aerosolization element is accomplishedusing a piezoelectric actuator.
 8. The method of claim 1, whereinaerosol production can be started within an interval of 20 millisecondsor less.
 9. The method of claim 8, wherein aerosol production can bestarted within an interval of 2 milliseconds or less.
 10. The method ofclaim 1, wherein controlling vibration of the aerosolization elementduring a certain interval of a breathing cycle further comprisesvibrating the aerosolization element continuously throughout thebreathing cycle.
 11. The method of claim 1, wherein controllingvibration of the aerosolization element during a certain interval of abreathing cycle further comprises vibrating the aerosolization elementonly during an entire inhalation phase.
 12. The method of claim 1,wherein controlling vibration of the aerosolization element during acertain interval of a breathing cycle further comprises vibrating theaerosolization element only during a predetermined portion of aninhalation phase.
 13. A system for providing a nebulized fluid to aspontaneously breathing or ventilated patient, the system comprising: anaerosolization element vibrating in the presence of a fluid, wherein theaerosolization element includes a plurality of apertures that nebulizethe fluid while the aerosolization element is vibrating; a breathingcircuit into which nebulized fluid is introduced when the aerosolizationelement is vibrating; and a controller that controls the vibration ofthe aerosolization element such that the aerosolization element vibratesduring a certain interval of a breathing cycle and does not vibrate attimes outside the interval; wherein the fluid comprises an antibioticthat is selected to treat a pulmonary infection resulting frommechanical ventilation, and wherein the interval is selected based onthe antibiotic.
 14. The system of claim 13, wherein the antibiotic is anaminoglycoside.
 15. The system of claim 14, wherein the aminoglycosideis amikacin.
 16. The system of claim 13, further comprising a sensorthat senses the patient's breathing cycle, the output of the sensor usedto recognize the interval.
 17. The system of claim 13, wherein theaerosolization element is vibrated piezoelectrically.
 18. The system ofclaim 13, wherein aerosol production can be started within an intervalof 20 milliseconds or less.
 19. The system of claim 18, wherein aerosolproduction can be started within an interval of 2 milliseconds or less.20. The system of claim 13, wherein the interval is the entire breathingcycle.
 21. The system of claim 13, wherein the interval is an entireinhalation phase.
 22. The system of claim 13, wherein the interval is apredetermined portion of an inhalation phase.
 23. A system for providingnebulized fluid to a ventilated patient, the system comprising: abreathing circuit; a vibratory aerosolization element having a firstface, a second face and a plurality of apertures therethrough, nebulizedfluid being introduced into the breathing circuit when theaerosolization element is vibrating; a controller configured to causevibration of the vibratory aerosolization element during a selectedinterval of a breathing cycle and not at times outside the selectedinterval; and a housing defining a reservoir containing the fluid to benebulized.
 24. The system of claim 23, wherein the housing is detachablefrom the breathing circuit.
 25. The system of claim 23, wherein thefluid comprises an antibiotic that is selected to treat a pulmonaryinfection resulting from mechanical ventilation.
 26. The system of claim25, wherein the interval is selected based on the antibiotic.
 27. Thesystem of claim 25, wherein the antibiotic is an aminoglycoside.
 28. Thesystem of claim 27, wherein the aminoglycoside is amikacin.
 29. Thesystem of claim 23, further comprising a breathing sensor that measuresthe patient's breathing cycle, the output of the breathing sensor beingused to identify the selected interval.
 30. The system of claim 23,wherein aerosol production can be started within an interval of 20milliseconds or less.
 31. The system of claim 30, wherein aerosolproduction can be started within an interval of 2 milliseconds or less.32. The system of claim 23, wherein the selected interval is an entirebreathing cycle.
 33. The system of claim 23, wherein the selectedinterval is an entire inhalation phase.
 34. The system of claim 23,wherein the selected interval is a predetermined portion of aninhalation phase.